Suitability of the limit dose in evaluating reproductive toxicity of substances and preparations.

An oral dose of 1000 mg/kg body weight/day is mentioned in Organisation for Economic Cooperation and Development (OECD) and European Union (EU) guidelines as a default maximum dose in limit tests for studies on reproductive toxicity. This paper investigated whether upper range human exposure data from the workplace are supportive of this limit dose as an upper limit of possible human exposure. To this end, published exposure data as well as data from the database MEGA of the German "Berufsgenossenschaften" were evaluated. These data indicate that exposure concentrations in the range of 500 to 2000 mg/m(3) (time-weighted averages) can be considered high human exposures to volatile compounds. Inhalation exposure to aerosols and dermal exposure result in lower dose levels. By applying suitable extrapolation factors, it was concluded that occupational exposures up to 325 mg/m(3) can reliably be assessed with limit tests using a dose level of 1000 mg/kg/day. The limit dose has been proposed for use in the EU as a starting point to derive specific concentration limits for hazard classification of preparations containing reproductive toxicants, with the objective to consider the potency of the substances. This analysis shows that for some groups of chemicals, instead of the limit dose, the putative maximum levels of human exposure should be taken into account when deriving concentration limits for the classification of preparations. Furthermore, possible deviations from a linear correlation between concentration in the preparation and exposure should be considered.